Protein kinases play important regulatory roles in numerous biological pathways controlling for example the cell cycle, cell division, metabolism, transcription and protein biosynthesis. The wide spread involvement of protein kinases in biology is underscored by links between dysregulated kinases and disease. A wide range of protein kinases have been identified as the critical drivers of various pathologies including cancer, diabetes, and inflammation. The cellular kinase signaling network is a major regulator of cancer progression: kinase signaling pathways are often co-opted for pathogenesis, and mutations in a large number of kinases have been identified as potent drivers of oncogenesis (Ding, L. et al., Nature, 2008. 455(7216): p. 1069-75; Greenman, C. et al., Nature, 2007. 446(7132): p. 153-8; Wood, L. D. et al., Science, 2007. 318(5853): p. 1108-13; Network, C. G. A. R., Nature, 2008. 455(7216): p. 1061-8). The paradigm for development of kinase inhibitor therapeutics in cancer has emerged from the success of Imatinib, which targets the single oncogenic kinase Bcr-Abl that directs Chronic Myelogenous Leukemia (CML) (Druker, B. J., Blood, 2008. 112(13): p. 4808-17). More generally, the architecture of kinase signaling networks provide multiple candidate targets for treatment of most cancer types (Knight, Z. A., H. Lin, and K. M. Shokat, Nat Rev Cancer, 10(2): p. 130-7; Manning, G. et al., Science, 2002. 298(5600): p. 1912-34). However, inhibition of specific kinases often provides only limited therapeutic efficacy. Although widely predicted to be successful, highly selective inhibitors of growth factor pathway-related kinases such as MEK1 or mitotic regulators such as Aurora B have been disappointing (Haura, E. B. et al., Clin Cancer Res., 16(8): p. 2450-7; Lorusso, P. M. et al., J Clin Oncol, 2005. 23(23): p. 5281-93; Pratilas, C. A. and D. B. Solit, Clin Cancer Res., 16(13): p. 3329-34; Rinehart, J. et al., J Clin Oncol, 2004. 22(22): p. 4456-62; Boss, D. S., J. H. Beijnen, and J. H. Schellens, Oncologist, 2009. 14(8): p. 780-93; Boss, D. S. et al., Ann Oncol., 22(2): p. 431-7). Sources of failure include rapidly emerging resistance as well as significant toxicity, which can limit dosing to levels insufficient to block tumor growth. The complexity of signaling networks and the challenge of attacking a tumor in the midst of multiple healthy organ systems that share many of the same pathway components has severely hampered the development of useful single target kinase inhibitors. By contrast most drugs approved for clinical use have multiple targets (Karaman, M. W. et al., Nat Biotechnol, 2008. 26(1): p. 127-32; Mestres, J. et al., Mol Biosyst, 2009. 5(9): p. 1051-7). For many or perhaps most, ‘off-target’ activities likely contribute to the drug's overall efficacy, although the mechanistic basis for this efficacy is known in only a small number of cases.
Phenotype-based drug discovery has historically been highly successful, but it has been largely supplanted by target-based discovery. Sorafenib provides a recent example of this mode of drug discovery (Lyons, J. F. et al., Endocr Relat Cancer, 2001. 8(3): p. 219-25). Sorafenib was initially developed as an inhibitor of Raf kinase, yet it showed little efficacy in mutant Ras- or Raf-driven tumors. The efficacy of Sorafenib in renal and hepatocellular cancer was later attributed to inhibition of the kinase VEGFR2 in endothelial cells and, potentially, PDGFR in pericytes; other targets may also play a role (Ahmad, T. and T. Eisen, Clin Cancer Res, 2004. 10(18 Pt 2): p. 6388S-92S; Liu, L. et al., Cancer Res, 2006. 66(24): p. 11851-8; Ostman, A. and C. H. Heldin, Adv Cancer Res, 2007. 97: p. 247-74).
Most MEN2 patients have an autosomal dominant activating mutation in the Ret (rearranged during transfection) receptor tyrosine kinase that is necessary and likely sufficient to direct a series of transformation events including medullary thyroid carcinoma (MTC), parathyroid adenoma, and pheochromocytoma (Lairmore, T. C. et al., Proc Natl Acad Sci USA, 1993. 90(2): p. 492-6; Almeida, M. Q. and C. A. Stratakis, Cancer Genet Cytogenet, 2010. 203(1): p. 30-6). The present invention provides solutions to these and other problems in the art.